As stated in our original grant application, in brief, our major objective is to study the active principle in the blood of animals and patients who have sustained an episode of severe shock, which is capable of killing recipients of this blood. In recent years we established that the material migrates electrophoretically with gamma globulin and behaves as aggregated (bound) gamma globulin upon ultracentrifugation, having an immunospecificity of gamma globulin and a molecular weight greater than 10,000. It is relatively heat stable and non dialyzable; chromatographically pure preparations are colorless, soluble in water and alcohols, non-TCA precipitable, consisting of 16 different amino acids, mostly acidic, an isoelectric point of about 49,000. At present it appears to be a glycopeptide. Physiologically it is able to kill recipient animals and demonstrates a remarkable toxicity to the heart, primarily by inhibition of ventricular contraction as demonstrated in the intact frog heart (which is used for our bioassay), the isolated perfused heart (Langendorf) and the in vivo dog (open-chest preparation) heart. It is our working hypothesis that during shock, the stagnation and hypoxia secondary to selective compensatory ischemia resultant from hemorrhage, causes an alteration in plasma protein(s) to form a "pretoxin" (CVTF-precursor); subsequently, upon perfusion of the lymphoid tissues (primarily the spleen) after transfusion of the patient or animal, white blood cell enzymes enter the circulation to cause the activation of the "pretoxin" to the Cardiovascular Toxic Factor (CVTF). We demonstrated that the best source of this white blood cell enzyme (other than our in vitro use of lysed white blood cells) is the effluent blood of the spleen of the hemorrhaged and transfused rat immediately following transfusion of its shed blood. In recent months we have demonstrated a similar factor in the blood that is normally stored. Both factors also have been demonstrated to cause renal dilation and anuria.